Gout

Definition

Disorder of purine metabolism characterised by hyperuricaemia and recurrent attacks of acute synovitis due to urate crystal deposition
Associated with accumulation of articular, osseous, cartilaginous and soft tissue crystalline deposits (tophi)

Aetiology

Hyperuricaemia is the common denominator of the syndrome (all patients with gout have hyperuricaemia)
If levels increase above its solubility® crystal deposition
Hyperuricaemia is present in 2 - 18% of the population but only 5% of patients with hyperuricaemia® gout

Primary Hyperuricaemia

(Secondary to disordered uric acid metabolism)
Accounts for 95%
Inherited disorder with over production (20%) or under excretion (80%)
Classification based on 24 hour urine collection and urate excretion

Secondary Hyperuricaemia

Gout is a secondary feature of a number of genetic, or acquired processes and accounts for 5% of cases
Over-production:
Myelo-proliferative and lympho-proliferative disorders
(polycythemia, thrombocytopenia, myeloid metaplasia, leukaemias, lymphomas, paraprotinaemias, haemolytic anaemias, pernicious anaemia, infectious mononucleosis)
Cytotoxic and radiation therapy for malignancy
Psoriasis

Under excretion:
Renal disease
Drugs (thiazide diuretics and low dose salicylates)
Hyper and hypoparathyroidism
Myxoedema

Contributing Factors:
Diabetes
Hypertension and coronary heart disease
Excessive alcohol intake
High purine diets
Obesity
Low urine volume with normal renal function

90% of patients with gout have a disorder of uric acid excretion and drugs that alter renal tubular function can contribute to the occurrence of gout (eg diuretics, aspirin, ethanol)

Diuretics are the most common cause of secondary hyperuricaemia due to volume depletion and enhanced tubular resorption of urate
Increased risk of developing the disease with increasing age and serum urate concentration
Genetic studies suggest multi factorial inheritance

Incidence

20 - 30 / 100,000
Prevalence 0.13 - 0.37 % of population
Male : Female 20:1 (5% of cases are female)
Males usually more than 35 years, women usually more than 55 years
Gout is the most common form of inflammatory disease in men over 30 years of age
Rarely seen before the menopause in women

Clinically

Stages of Disease
  1. Asymptomatic hyperuricaemia
  2. Acute gouty arthritis
  3. Inter-critical gout
  4. Chronic tophacious gout

Acute Attack

Sudden attack of joint pain lasting several days
May follow trauma, surgery, drugs, exercise or alcohol
Commonly affects MTP joint of great toe (at least 50% of initial attack and 90% at some stage), also ankle and finger joints and the olecranon bursa
Joints feel hot and extremely tender
Hyperuricaemia is present at some stage
7% never have a second attack
60%® recurrent attack within one year
Negative birefringent crystals are seen in synovial fluid® diagnosis
X-Rays: Soft tissue swelling

Chronic Gout

Recurrent attacks® poly-articular gout, usually more severe, more prolonged and associated with fever
May be difficult to differentiate from other inflammatory arthropathies or infection

Joint erosions® chronic pain, stiffness and deformity
Tophi may appear around joints, olecranon and pinna of the ear
May ulcerate through the skin® discharge chalky material
Only a minority of patients develop visible tophi, permanent joint changes or chronic symptoms
Renal calculi may form and parenchymal renal disease occur secondary to crystal deposition with some renal dysfunction occurring in 90% of patients with gouty arthritis
In 10% gout is preceded by nephrolithiasis
Typically the first attack occurs during the night and tends to subside after 3 - 10 days
Tophi generally noted an average of 10 years after the first attack

X-Rays:
Symmetrical punched out cysts in extra-articular bone
Bony erosions either extra-articular or articular
Joint space is preserved until late in the disease

Pathology

Histopathology

Tophi® chronic foreign body granulation tissue surrounding urate crystals
Uric acid crystals deposited in synovium, tendons and tendon sheaths and articular cartilage
Results in activation of acute inflammation® cartilage degeneration and peri-articular cysts formation secondary to deposition of mono-sodium urate
Large cartilage and soft tissue tophi appear

Investigations

If excretion of uric acid is greater than 750mg per 24 hours suggests over production of urate
Measure 24 hour urate excretion after 1 week of a purine free diet® over production if more than 600mg and under excreter if less than 350mg per 24 hours
Synovial fluid® high cell count more than 90% neutrophils
Urate crystals usually remain in the synovium after the acute attack has settled

Compensated polarised light microscopy

With polarising filters and a first order red compensator monosodium urate crystals are 3-20mm in length needle shaped and strongly negatively birefringent (yellow in colour when the crystal axis is parallel to the compensator)
Calcium pyrophosphate crystals are short, rhomboidal and weakly positively birefringent (blue when the crystal axis is parallel to the compensator)

Differential Diagnosis

Infection
Reiters disease
Pseudo-gout (tends to affect large rather than small joints)
Rheumatoid arthritis
Arthritis mutilans

Treatment

Aim of therapy

  1. Terminate the acute attack
  2. Prevent or reduce the frequency of acute gouty attacks
  3. Prevent or reverse the complications of the disease (tophi and organ damage)
  4. Prevent renal damage

Therapy indicated for frequent acute attacks where serum urate more than 0.48 mmol/L, to control chronic tophacious gout, renal complications or arthropathy
Rest joint

Colchicine

Falling out of favour (®diarrhoea)
Dose:
1mg followed by 0.5mg every 2 - 3 hours and stop when pain dissapears or GIT symptoms develop (usually 4 - 10mg total)
Prophylactic use 0.5 - 2mg nightly or every second night

Indomethicin

Useful in the treatment of acute gout
Dose:
75mg stat followed by 50mg qid (4 doses), 50mg tds (3 doses), and then 25mg tds

Probenicid

(Uricosuric agent) In the presence of normal renal function® increased secretion of uric acid
Dose;
250mg bd increasing to desired level over several weeks. Usually 1gm per day, max 3gm per day
Uricosuric action blocked by aspirin
Maintain high urine flow and alkalinise the urine to prevent renal precipitation and calculi

Toxicity:
GIT irritation
Allergic dermatitis
Generally less toxic than allopurinol

Allopurinol

(xanthine oxidase inhibiter) Blocks production of uric acid from xanthine® decreased excretion of uric acid and therefore useful in renal insufficiency or patients with renal calculi

Dose:
300mg per day (Half life 2-3 hours but active metabolite 18-30 hours and as renal excretion decrease dose in renal disease)

Toxicity:
Occurs in 20% and in 5% need to stop therapy
Exfoliative dermatitis
Interstitial nephritis
Peripheral neuropathy
Necrotising vasculitis
Bone marrow aplasia
Hepatotoxicity

Choice of therapy depends on aetiology of increased uric acid
Under secretors® uricosuric agents which are contraindicated in patients with renal complications.
Treat over producers and those with renal complications with allopurinol (decrease the dose in renal impairment)

Allopurinol and uricosuric agents may be used in combination
Both groups of drugs may precipitate an acute attack and should not be commenced unless under the cover of an anti-inflammatory which should be continued until tophi have resolved

Need to warn patients of the possibility of a flare up during the early stages of their therapy
Every 6/12 check BP, serum uric acid and blood urea and creatinine if commenced on treatment
less than 1 attack per year® no indication for prophylaxis
more than 5 attacks per year® prophylaxis indicated

Chondro-calcinosis

Deposition of calcium pyrophosphate dihydrate crystals in joint tissue® acute and chronic inflammatory joint disease
The acute form = Pseudo-gout

Aetiology

  1. Hereditary (Autosomal dominant)
  2. Idiopathic
  3. Associated with various metabolic disorders

Incidence

Affects males and females equally
Usually more than 50 years
Increased incidence with increased age
3 - 5% of population have CPPD deposition in the knee at autopsy
Seen in 40% of patients with haemochromatosis or hyperparathyroidism

Clinically

Presents with acute gout like episode in about 30%
Attack develops over 12 - 36 hours and persists for 1-2 weeks
5%® pseudo-rheumatoid appearance
50%® chronic disease with progressive joint degeneration (ordinary degenerative osteoarthritis or degenerative spondylosis)
The remainder remain asymptomatic
Knee is usual site (accounts for ~ 50%) but other larger joints may be affected
Inflammation of one or more joints lasting several days and usually less severe than gout.
May present in association with true gout
Seldom affects the great toe
Diagnosis confirmed by positively birefringent crystals in synovial fluid (Gout negative)
Chronic chondrocalcinosis is usually asymptomatic but may® poly-articular osteoarthritis
X-Rays:
Calcification of articular cartilage and fibro-cartilaginous structures (menisci, TFCC, symphysis pubis, inter-vertebral discs
Punctate, or linear densities in articular hyaline cartilage or fibro-cartilage
Fine calcified line separate from the subchondral plate in hyaline cartilage
In fibro-cartilage® thick irregular densities and in tendons calcifications are linear
®development of degenerative changes

Investigations

Synovial fluid inflammatory with 50-500cells /mm3 (degenerative arthritis is usually non inflammatory)
Need to exclude associated diseases
Gout
Hyperuricaemia
Diabetes mellitis
Haemochromatosis
Ochronosis
Hyperparathyroidism
Wilsons disease
Acromegaly
Hyperphosphatasia
Hypothyroidism
Degenerative joint disease

Pathology

Initial site of crystal formation is believed to be in the articular cartilage around chondrocytes which are then extruded into the joint® inflammatory reaction
Commoner in aged and abnormal cartilage therefore often associated with other arthritidies

Cause of crystal shedding believed to be a sudden change in the ionic calcium and pyrophosphate equilibrium in cartilage eg acute injury, illness, operation or inflammatory arthritis

Often precedes and assumed to predispose to the development of OA
About 1/3 associated with inter-vertebral disc calcification
CPPD crystals are short blunt rods which are weakly birefringent under compensated polarised light in contrast to the strongly negative birefringence of urate crystals

Differential Diagnosis

Hyper-parathyroidism® hypercalcaemia and sub-periosteal erosion's
Haemochromatosis® degenerative, progressive arthritis of finger joints with calcification in multiple joints on X-Ray and associated with inter-vertebral disc calcification and increased serum iron
Ochronosis (IBEM; due to absence of homogentisic acid oxidase) presents around the 4th decade with pain and stiffness of large joints and the spine® inter-vertebral disc calcification and ankylosis.
Homogentisic acid in urine® turns black when left standing

Treatment

Rest
Anti-inflammatory therapy (NSAIDs, corticosteroid injection)
Chronic chondrocalcinosis appears to be irreversible
Treatment for secondary OA

Hydroxy-apatite Crystals

Secondary to deposition of calcium hydroxy-apatite crystals
Tend to affect one or only a few joints where CPPD is more generalised and depositions have a more diffuse and amorphous pattern
Usually seen in the knee or shoulder
Hydroxy-apatite crystals cannot be recognised by light microscopy as they are too small